This invention is concerned with the localization or differentiation of cancerous tumors or other neoplasms as they occur, for example, in colorectal cancer and additionally in dealing with other cancer occurrences.
Colorectal cancer has been the subject of extensive investigation over the past 30 years and the effort thus far has achieved little change in mortality rates. Generally, statistics have shown that from 1964 through 1973, the five-year survival rate for the illness was 77% in patients with localized cancer, and only 47% in patients with all stages of this disease. Concerning the above statistics, see the following publication:
I. "1983 Cancer Statistics", Ca-A Journal for Clinicians, published by The American Cancer Society, 33(1), 1983. PA1 II. Day, E. O.; Planisek, J. A.; Pressman D: "Localization of Radioiodinated Rat Fibrinogen in Transplanted Rat Tumors", J. Natl. Cancer Inst. 23: 799-812, 1959. PA1 III. Sparr, J. L.; Bale, W. F.; Marrock, D. D.; Dewey, W. O.; McCardle, R. J.; Harper, P. V.; "Labelled Antibodies to Human Fibrinogen. Diagnostic Studies and Therapeutic Trails", Cancer, 20: 865-870, 1967. PA1 IV. Goldenber, D. M.: "Oncofetal and other Tumor-associated Antigens of the Human Digestive System", Curr. Top. Pathol. 63: 289-342, 1976. PA1 V. Goldenberg, D. M.; Deland, F,; Kim, E. E.: "Human Chorionic Gonadotrophin Radioantibodies in the Radioimmunodetection of Cancer and the Disclosure of Occult Metastases" Proc. Nat'1. Acad. Sci. 78: 7754-7758, 1981. PA1 VI. Goldenberg, D. M.; Deland, F.; Kim, E. E., et al.: "Use of Radiolabelled Antibodies to Carcinoembryonic Antigen for the Detection and Localization of Diverse Cancers by External Photoscanning", N. Engl. J. Med. 298: 1384-1388, 1978. PA1 VII. Goldenberg, D. M.; Preston, D. F.; Primus, F. J.; Hansen, H. J.: "Photoscan Localization of GW-39 Tumors in Hamsters Using Radiolabelled Anticarcinoembryonic Antigen Immunoglobulin" J. Cancer Res. 34: 1-9, 1974. PA1 VIII. Goldenberg, D. M.; Sharkey, R. M.; Primus, F. J.: "Carcinoembryonic Antigen in Histopathology: Immunoperoxidase Staining of Conventional Tissue Sections", J. Natl. Cancer Inst. 57: 11-22, 1976. PA1 IX. Gold, P., Freedman, S. O.: "Demonstration of Tumor Specific Antigen in Human Colonic Carcinomata by Immunologic Tolerance and Absorption Techniques", J. Exp. Med. 121: 439-462, 1965. PA1 X. Dhar, P.; Moore, T.; Zamcheck, N.: "Carcinoembryonic Antigen (CEA) in Colonic Cancer. Use in Pre-operative and Post-operative Diagnosis and Prognosis" JAMA 221: 31-35, 1972. PA1 XI. Joyce, S.; Lobe, T.; Martin, E. W. Jr.: "Direct Carcinoembryonic Antigen Assay in Diagnosis and Prognosis", Surgery 86: 627, 1979. PA1 XII. Herrera, M. D.; Chu, T. M.; Holyoke, E. D.: "Carcinoembryonic Antigen (CEA) as a Prognostic and Monitoring Test in Clinically Complete Resection in Colorectal Carcinoma", Ann. Surg. 183: 5-9, 1976. PA1 XIII. Halsal, A. K.; Fairweather, D. S.; Bradwell, A. R. et al: "Localization of Malignant Germ-Cell Tumors by External Scanning After Injection of Radiolabelled Anti-Alpha-Feto-protein" Br Med J. 283: 942-944, 1981. PA1 XIV. Sullivan, D. C.; Silva, J. S.; Cox, C. E. et al: "Localization of I-131 Labelled Goat and Primate Anti-Carcinoembryonic Antigen (CEA) Antibodies in Patients with Cancer" Invest Radiol 17: 350-355, 1982.
Notwithstanding the above less than desirable statistics, these lengthy investigations into the disease have evolved a variety of (a) tests, (b) of quite sophisticated radiological equipment and (c) of surgical protocols. As part of the investigations, the various, somewhat time defined, stages of colon cancer have been categorized in a sequence of A through D known as "Dukes Classification". When the colonic tumors can be found early, ie. types A and B tumors, the lesion can be isolated and the success rate for surgery is impressive. However, for more advanced tumors which are categorized at C and D levels, localization has been seen to be quite difficult and this difficulty represents a significant factor in the generation of the above statistics.
Looking to the history of the above-noted investigations, the use of radio-labelled immunoglobulin for tumor localization was shown to be possible in 1959 when Day et al. radiolabelled isolated antifibrin. See in this regard the following publication:
Fibrin, while not a tumor-specific antigen, was known to have a frequency of presence in tumors due to the inflammatory process accompanying invasion. This work demonstrated that a protein in high concentration in tumor sites could be used to localize tumors. The antibodies against human fibrin and ferritin were used in attempts to employ specific immunoglobulins for diagnosis. Spar, in 1967, performed scans in 179 patients using rabbit immunospecific antifibrin antibody and 113 of these tumor scans were positive. See the following publication in this regard:
The lack of a direct association with the neoplastic process and the lack of specificity for any one neoplasm are the failings of the use of a fibrin antibody. Attempts to use rabbit antiglioma antibody by intracarotid infusion of radiolabelled immunoglobulin were associated with limited success, and the specificity of the antiserum was questionable.
Goldenberg, et al. published the successful results of their initial clinical trail of tumor detection and localization by scintillation scanning of patients injected with I.sup.131 -labelled heterologous(goat) antibodies to human carcinoembryonic antigen (CEA). See the following publications in this regard:
Tumor location could be demonstrated at 48 hours after the I.sup.131 -anti-CEA injection in almost all patients. See the following publications in this regard:
Of particular importance in connection with this investigation, ordinary scintigrams proved difficult to interpret because of blood-pool background radioactvity. Computer subtraction of radioactive blood-pool agents from the I.sup.131 -labelled heterologous (rabbit) antibody to human CEA was attempted to enhance imaging.
The noted carcinoembryonic antigen (CEA) is a tumor-associated antigen of gastrointestinal cancer and was first described by Gold et al. in 1965. See the following publication in this regard:
The carcinoembryonic antigen, so named because of its noted presence in neoplastic and embryonic gastrointestinal tissues, has been characterized as a protein-polysaccharide complex. Clinical experience with CEA has shown that, while its marker function may also be present in non-malignant disease states, an increase in CEA levels with colon and pancreatic tumors is well established and serial CEA determinations have become a highly useful diagnostic tool. See the following publication in this regard:
Investigations have shown that a high correlation exists between the level of circulating CEA and the extent of tumor. After resection presumed to be curative, CEA levels may fall or become undetectable; as tumor recurs, the CEA levels rise. A new low CEA level (baseline) is reached 7 to 30 days post-operatively, and any significant rise above this indicates tumor recurrence or progression. See the following publications in this regard:
The use of radionuclide labelling of antibodies in conjunction with radio-detection equipment has continued to be the subject of development and study. In the recent past, advances in the technique are evidenced by the pursuit of the use of monoclonal antibodies or fragments thereof with a variety of radionuclides. Several techniques for imaging these antibodies are in use, for example tomographic scanning, immunoscinctigraphy, and the like. The particular choice of radionuclide for labelling antibodies is dependent upon its nuclear properties, the physical half-life, the detection instruments's capabilities, the pharmacokinetics of the radiolabelled antibody, and the degree of difficulty of the labelling procedure. Generally, there are trade-offs of advantages and disadvantages with the election of any given radionuclide. The most widely used of these radionuclides in nuclear medicine imaging include Technetium Tc.sup.99m, Iodine I.sup.123, I.sup.131, and Indium In.sup.111.
For the most part, the endeavors to the present time in using antibodies to localize tumors of the gastrointestinal tract use the radionuclide I.sup.131 as the marker or label. See publication VI above and the following publications:
In spite of its somewhat extensive utilization, I.sup.131 is not an ideal radionuclide for use in diagnostic medicine. The high energy gamma-photon emitted from I.sup.131 is poorly detected by current instrumentation. In addition, the particulate emissions of I.sup.131 deliver a high radiation dose to the patient. Other radionuclides of iodine have been considered not to be ideal for gamma camera or the like imaging of the biodistribution of radiolabelled antibodies because of the short physical half-life (27-35 kev) (I.sup.123 :13.2 hours) (27-35 kev) or very low energy gamma emission as will be evidenced with the use of I.sup.125.
In effect, the external imaging techniques for detecting cancerous tumors using radiolabelled antibodies (e.g. to CEA) have been of minimal value to the surgeon. As a consequence, the surgical approaches in use resort to the dated procedures of vision and touch (palpation) in combination with locally determined protocols dictating the extent of tissue resection.
Tissue removed by resection during surgery includes not only tissue suspected by the surgeon of being neoplastic, but also includes an amount of healthy tissue taken because the precise tumor margins cannot be ascertained by the surgeon. Coupled with the devastating risk of not removing neoplastic tissue resulting in tumor recurrence, surgical protocol dictates that healty tissue be taken in order to ensure the removal of neoplastic tissue. Of course, the final determination as to whether the resected tissue is malignant falls to the pathologist who receives the tissue removed during the surgical procedure. Often, the pathologist will subject the tissue to immediate clinical observation and palpation in order to select a suitable site for more extensive tests to be conducted, e.g. a frozen section test. Often, the surgeon awaits the pathologist's decision before proceeding with a complete resection. Even following surgery, the pathologist's report is extremely important in confirming post-operative treatment of the patient. Too, the surgeon often looks to the pathologist to confirm that the margins of tissue removed are free of neoplastic tissue.